CNS Deficits: Interaction of Age and Alcoholism

中枢神经系统缺陷：年龄和酗酒的相互作用

• 批准号: 7883726
• 负责人: Adolf Pfefferbaum
• 金额: $ 39.84万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883726
• 关键词: Accounting; Acute; Affect; Age; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Animals; Anterior; Anterior Nuclear Group; Area; Autopsy; Brain; Brain Injuries; Brain Pathology; Brain region; Caliber; Cell Nucleus; Cerebellar vermis structure; Cognitive; Corpus Callosum; Development; Diffusion Magnetic Resonance Imaging; Dose; Dysmorphology; Ethanol; Fiber; Fimbria of hippocampus; Goals; High Prevalence; Hippocampus (Brain); Human; Image; Incidence; Individual; Individual Differences; Inferior; Inferior Colliculus; Lesion; Life; Literature; Location; Magnetic Resonance Imaging; Malnutrition; Measures; Modeling; Motor; Myelin; Necrosis; Neuronal Plasticity; Neurons; Nutritional status; Pathology; Pattern; Predisposition; Pyrithiamine; Rattus; Recording of previous events; Recovery; Reporting; Resolution; Risk; Rodent; Site; Source; System; Testing; Thalamic structure; Thiamine; Thiamine Deficiency; Translations; Wernicke Encephalopathy; Wernicke-Korsakoff Syndrome; alcohol effect; alcohol exposure; anterior commissure; base; binge drinking; brain tissue; density; dietary control; drinking; fimbria; frontal lobe; in vivo; mortality; neurogenesis; neuropathology; neurotoxic; neurotoxicity; nutrition; problem drinker; white matter

There is considerable variability in the neuroradiologicalsigns of neuropathology of alcoholism; some individuals have massive brain shrinkage and others little demonstrable effect. A relationship between total lifetime alcohol dose and brain tissue volume shrinkage or CSF space expansion is typically elusive and does not account for a substantial portion of the dysmorphology. Autopsy incidence of Wernicke's encephalopathy (WE) associated lesions, undetected in life, suggests an underappreciation of the high prevalence of nutritional deficiency (especially thiamine) among alcoholics. Further, the neuroradiological findings of uncomplicated (i.e., nonamnesic) alcoholics appear as a graded version of those seen when WE progresses to the amnesic Korsakoff syndrome (KS or WKS). The human literature is sprinkled with references to the "neurotoxicity of alcohol" but with little direct support for this assertion and with the following questions begged: is alcohol neurotoxic if nutrition is adequate, or do repeated bouts of subclinical nutritional deficiency underlie human alcoholic neuropathology? Animal models demonstrate acute neuronal necrosis after binge alcohol, but at very high doses in alcohol naive animals, sometimes with significant mortality. Alcohol effects are primarily described in the hippocampal-entorhinal-olfactory circuit, known for its neuroplasticity, neurogenesis and unique susceptibility to environmental insult. Thiamine deficiency studies in rodents consistently produce substantial brain pathology, including white matter and cortical lesions, typical of human alcoholics in vivo and at autopsy, but also have a signature lesion pattern involving the mammillothalamic tract, including the mammillary bodies, fornix, anterior thalamic nuclei, in addition to the superior and inferior colliculi and anterior superior vermis. We propose to develop a translational animal model, using high resolution structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to examine thiamine deficiency, modeled as controlled dietary plus pyrithiamine-induced thiamine deficiency (PITD), acute binge ethanol treatment and their interaction in rats. We will also study WKS-at-risk alcoholics with repeated sustained binge drinking and historical reporting of poor nutrition during the binges. The overarching hypothesis is that nutritional deficiency makes as great or greater contribution than alcohol per se to the observed neuropathology, and the combination is synergistically damaging. We propose four specific aims: Specific Aim 1: Measure the development, extent, location and recovery of neuroradiologically-detectable brain damage with repeated bouts of PITD in rats. Specific Aim 2: Measure the effects on the hippocampus and fimbria of repeated 5-day, acute alcohol binge in rats. Specific Aim 3: Model human drinking in rats with combined alcohol binges plus thiamine deficiency. Specific Aim 4: Translation from rats to humans: Identify neuroradiological signs of nutritional deficiency compounding alcoholism-related dysmorphology in human alcoholics.

酒精中毒神经病理学神经放射学的差异很大。一些 个人的大脑收缩率很大，其他人几乎没有证明的作用。总和之间的关系 终身酒精剂量和脑组织体积收缩或CSF空间扩展通常难以捉摸，并且 不解释畸形学的很大一部分。 Wernicke的尸检率 脑病（我们）相关的病变在生活中未被发现，这表明高度不足 酗酒者中营养缺乏症（尤其是硫胺素）的患病率。此外，神经放射学 简单的发现（即非Amnesic）酗酒的发现是当我们看到的分级版本 发展为健忘症科萨科夫综合征（KS或WKS）。人类文学散布着 引用“酒精的神经毒性”，但对此主张几乎没有直接支持，并以下内容 乞讨的问题：如果营养足够，还是在亚临床营养中反复出现，是酒精神经毒性吗 缺乏人类酒精神经病理学？ 动物模型表现出暴饮精酒后急性神经元坏死，但酒精的剂量很高 天真的动物，有时死亡。酒精作用主要在 海马 - 静脉 - 富特电路，以其神经塑性，神经发生和独特的敏感性而闻名 对环境侮辱。啮齿动物的硫胺素缺乏研究始终产生大脑 病理学，包括白质和皮质病变，体内和尸检的典型人类酒精药物 还具有涉及乳腺丘脑的签名病变模式，包括乳腺体， 前丘脑前核核，除了上和下丘脑和前毛皮外。 我们建议使用高分辨率结构磁共振开发转化动物模型 成像（MRI）和扩散张量成像（DTI）检查硫胺素缺乏，以控制为模型 饮食加硫胺素引起的硫胺素缺乏症（PITD），急性暴饮暴食及其 大鼠的相互作用。我们还将以一再持续的暴饮暴食和 在bing虫期间营养不良的历史报道。总体假设是营养 与观察到的神经病理学的饮酒本身相比，缺乏症具有巨大或更大的贡献，并且 该组合有协同损害。我们提出了四个具体目标： 特定目的1：衡量神经放射学检测的发展，范围，位置和恢复 脑损伤，大鼠反复发作。 特定目标2：测量对重复的5天，急性酒精的海马和纤维膜的影响 在老鼠中暴饮暴食。 特定目标3：与酒精bing剂和硫胺素缺乏症的大鼠中的人类饮酒建模。 特定目的4：从大鼠到人的翻译：识别营养缺乏的神经放射学迹象 人类酗酒者中与酒精中毒相关的畸形学。